1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to the use of substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans as positive modulators of AMPA receptors, and for the treatment of neurodegenerative conditions, for the treatment of schizophrenia, and as cognitive enhancers.
2. Related Background Art
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropic.xe2x80x9d This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonist N-methyl-aspartate (NMDA), xcex1-amino-3-hydroxy-5-methyoisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced phosphoinositide hydrolysis in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic connections during development, but also changes in the efficiency of synaptic transmission throughout life. See Schoepp, Bockaert, and Sladeczek, Trends Pharm. Sci. 11: 508 (1990); McDonald and Johnson, Brain Res. Rev. 15: 41 (1990).
There is much evidence suggesting that the interaction of glutamate with membrane receptors plays a key role on many critical neurological functions such as cognition, learning and memory. Cognitive deficits likely arising from hypoactivity of glutamate receptors are known to be associate with neurodegenerative disorders such as Alzheimer""s disease. Hypoactivity of glutamate receptors also might be associated with schizophrenia. One therapeutic approach is the direct stimulation of glutamate receptors with agonists. However, this approach increases the risk of excitotoxicity and may lead to further neurodegeneration. Selective positive modulation of certain glutamate receptor subtypes would be a better approach. Therefore positive modulators of AMPA receptors are expected to be useful for the treatment or amelioration of a number of chronic neurologic disorders such as schizophrenia, Alzheimer""s disease and malnutrition, as well as neural maldevelopment (Thomas, R. J., J. Am. Geriatr. Soc. 43:1279-1289 (1995)). It has been shown that the AMPA receptor positive modulator BDP 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine and its derivatives enhance memory in rat (Staubli et al., Proc. Natl. Acad. Sci. 91:777-778 (1994)). The AMPA-positive modulator BDP-29 also has been shown to attenuate the amount of stereotypic rearings seen in rats after methamphetamine injection, suggesting that AMPA receptor modulators might be useful for the treatment of schizophrenia (Larson et al., Brain Res. 738:353-356 (1996)). Furthermore, piracetam, a well-known nootropic agent, which is used to treat cognitive impairment in the elderly, was found to be a positive modulator of AMPA receptors (Copani et al., J. Neurochem. 58:1199-1204 (1992)). A recent clinical study showed that piracetam was effective in treating patients with myoclonus, especially that of cortical origin (Ikeda et al., Movement Disorders 11:691-700 (1996)). Thus, AMPA receptor positive modulators are expected to be useful in treating myoclonus.
Desai et al. (Neurophamacology 34:141-147 (1995)) reported that the memory-enhancing agent 1-BCP selectively potentiates AMPA-induced [3H]norepinephrine release in rat hippocampal slices. 
Zivkovic et. al. (J. Pharmacol. Exp. Therap, 272:300-309 (1995)) reported that the cognitive enhancer IDRA 21 attenuates AMPA receptor desensitization. 
Yamada et. al (Brit. J. Pharmacol, 117:1663-1672 (1996)) reported that cyclothiazide blocks AMPA receptor desensitization and potentiates AMPA receptor gated currents. 
The invention relates to the discovery that the compounds represented by Formula I are positive modulators of xcex1-amino-3-hydroxy-5-methyoisoxazole-4-propionic acid (AMPA) receptors. A first aspect of the invention is directed to method for treating a disorder responsive to the positive modulation of AMPA receptors in animals suffering therefrom, comprising administering to an animal in need thereof a compound of Formula I: 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 and R2 are independently hydrogen, C1-10 alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl or thioalkyl; or R1 and R2 are taken together to form a carbocycle or heterocycle;
R3 is hydrogen, or C1-10 alkyl;
R4 is substituted or unsubstituted aryl or heteroaryl, carbocycle or heterocycle;
X is hydrogen, NO2, CN, C1-10 alkyl, haloalkyl, aryl, heteroaryl, COR, CO2R and CONRxRy,
wherein R, Rx and Ry are independently hydrogen, C1-10 alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl; or Rx and Ry are taken together to form a heterocycle;
Y is NH2, NHR, and NHCOR; and
Z is O and S.
These compounds can be used as cognitive enhancers, for the treatment of neurodegenerative diseases, including Alzheimer""s disease, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, AIDS associated dementia and Down""s syndrome as well as for the treatment of schizophrenia and myoclonus. A further aspect of the present invention is to provide a method for treating, preventing or ameliorating neurodegenerative diseases, including Alzheimer""s disease, amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, AIDS associated dementia and Down""s syndrome as well as for the treatment of schizophrenia and myoclonus by administering a compound of Formula I to a mammal in need of such treatment.
A further aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the positive modulation of AMPA receptors, comprising an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents.
A number of compounds useful in the present invention have not been heretofor reported. Thus, the present invention is also directed to novel substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans of Formula I. Further, the present invention is directed to 3H and 14C radiolabeled compounds of Formula I and their use as radioligands for their binding site on the sodium channel.